Background: Doxorubicin has been the traditional standard therapy for treatment of advanced soft tissue sarcoma (STS). The addition of cytotoxic agents leads to increased toxicity with minimal improvement in efficacy. Pembrolizumab monotherapy has demonstrated activity and tolerability in previous study of advanced STS. This study combined pembrolizumab with doxorubicin to determine safety and efficacy in the frontline setting. Methods: This single-center, single-arm, phase 2 trial enrolled subjects with unresectable or metastatic STS and no prior anthracycline therapy. Subjects were treated with pembrolizumab 200 mg IV and doxorubicin 60 mg/m2 (75 mg/m2 dose escalation per investigator discretion) IV every 3 weeks. The primary endpoint of safety, based on Bayesian stopping rules, evaluated if the severe or life-threatening treatment emergent adverse event (TEAE) rate exceeded 0.55. Secondary endpoints included overall survival (OS), objective response rate (ORR), and progression free survival (PFS). Efficacy and safety were based on RECIST 1.1 and CTCAE v 4.0, respectively. Kaplan-Meier methods evaluated time to event outcomes. Results: From 4/2017 to 12/2019, 30 subjects (53% female, median age 61.5 years, 10 patients > 70 years (33%)) were enrolled in the study with 6 (20%) patients still on treatment and 27 evaluable for response. The most common histologic subtypes were leiomyosarcoma (33%) and liposarcoma (23%), and a majority of patients demonstrated high grade disease (60%). Current analysis shows a median follow-up of 9.9 months. One subject experienced a stopping rule event (grade 3 autoimmune disorder). ORR was 33% (95% CI 17-54%), with documented disease control in 78% (95% CI 57.7-91.4%) of patients. Eight (30%) patients achieved a partial response, one (4%) patient achieved a complete response and 12 (44%) patients had stable disease. Preliminary results demonstrate median PFS of 6.9 months (PFS-6 mo: 52%) and median OS of 15 months (OS-6 mo: 81%) compared to historical PFS-6mo of 4.6 months and OS of 12.8 months with doxorubicin alone.¹ Most common grade 3+ TEAEs included neutropenia (11 [37%]), febrile neutropenia (6 [20%]), anemia (5 [17%]), and nausea (4 [13%]). Molecular and biomarker analysis is currently in progress. Conclusions: The combination of pembrolizumab with doxorubicin has manageable toxicity and preliminary promising activity in the treatment of anthracycline-naive advanced soft tissue sarcomas. Ref: 1. Lancet Oncol. 2014 Apr; 15(4):415-23. Clinical trial information: NCT03056001.